The overall objective of this proposal is to define the antigenic, allorecognition and functional sites of human Ia antigens by using antibodies of predetermined specificity, i.e. directed to small synthetic peptides comprising hydrophilic regions of the amino acid sequence of these antigens. An effort will be made to delineate those regions of the HLA-DR2 Beta chain which constitute antigenic sites as well as those that are involved in expressing the serologically defined polymorphism of this molecule. An attempt will also be made to define those antigenic sites which distinguish HLA-DR from HLA-DC antigens by using antibodies to distinct peptides of Alpha chain of HLA-DC antigens in binding and inhibition of binding assays against appropriate target cells and purified antigens. A third major aim is to use these antibodies of predetermined specificity to delineate functional regions of human Ia antigens. This will be accomplished by determining whether small synthetic peptides comprising defined regions of HLA-DR and HLA-DC antigens can mimic intact Ia molecules as stimulators of alloreactive T cell clones and whether antibodies directed to these peptides can inhibit the response of cloned Ia-restricted T cell lines. It is anticipated that these studies will aid in providing a better understanding of the relationship between primary structure of human Ia antigens and their functions in the immune response.